The efficacy of topical thiocolchicoside (Muscoril®) in
the treatment of acute cervical myofascial pain syndrome:
a single-blind, randomized, prospective, phase IV clinical study
Servikal miyofasiyal ağrı sendromunun tedavisinde topikal tiyokolşikosid'in
(Muscoril®) etkinliği: Tek-kör, randomize, prospektif, faz IV klinik çalışma
Ayşegül KETENCİ,1 Hande BASAT,1 Sina ESMAEİLZADEH1
Summary
Objectives: Myofascial pain syndrome is a disorder characterized by hypersensitive sites called trigger points at one or more
muscles and/or connective tissue, leading to pain, muscle spasm, sensitivity, rigor, limitation of movement, weakness, and rarely, autonomic dysfunction. Various treatment methods have been used in the treatment of myofascial pain syndrome. Among these, stretch and spray technique, trigger point injection, dry needling, pharmacological agents, and physical therapy modalities have been proven effective.
Methods: Sixty-five patients with acute myofascial pain syndrome were recruited into the study. Patients were randomized
into three groups. The first group received thiocolchicoside ointment onto the trigger points, the second group received 8 mg thiocolchicoside intramuscular injection to the trigger points, and the third group received both treatments. Treatment was applied for 5 consecutive days. Algometric and goniometric measurements and pain severity assessments with visual analog scale (VAS) were repeated on the first, third, and fifth days of the treatment.
Results: Pain severity measured with VAS significantly improved after the first day in the mono-therapy groups and after the
third day in all groups. While significant improvement was observed in all three groups in right lateral flexion measurements, no significant changes were observed in the combined treatment group in left lateral flexion measurements.
Conclusion: Thiocolchicoside can be used in the treatment of myofascial pain syndrome. The ointment form may be a good
alternative, particularly in patients who cannot receive injections.
Key words: Local injection; medical treatment; muscle relaxant; myofascial pain syndrome; trigger point.
Özet
Amaç: Miyofasiyal ağrı sendromu, bir veya birkaç kas ve/veya bağ dokusunda bulunan ve tetik nokta denilen hipersensitif bölgelerle kendini gösteren; ağrı, kas spazmı, hassasiyet, sertlik, hareket kısıtlılığı, güçsüzlük ve nadiren otonomik disfonksiyon yapabilen bir rahatsızlıktır. Miyofasiyal ağrı sendromunun tedavisinde çeşitli tedavi yöntemleri kullanılmıştır. Bu tedaviler arasında germe ve sprey tekniği, tetik nokta enjeksiyonu, kuru iğneleme, çeşitli ilaç tedavileri ve fizik tedavi yöntemlerinin etkinliği gösterilmiştir.
Gereç ve Yöntem: Çalışmaya akut miyofasiyal ağrı sendromulu 65 hasta alındı. Hastalar üç gruba randomize edildi. İlk gruba tetik noktalar üzerine tiyokolşikosid merhem, ikinci gruba tetik noktalar üzerine tiyokolşikosid ampul intramuskuler, üçüncü gruba ikisi birlikte uygulandı. Tedaviler beş gün boyunca yapıldı. Algometrik ve goniometrik ölçümler, vizüel analog skala (VAS) ile ağrı şiddeti değerlendirimi birinci, üçüncü ve beşinci günde yapıldı.
Bulgular: VAS ile ölçülen ağrı şiddeti birinci günden itibaren monoterapi gruplarında, üçüncü günden itibaren tüm gruplarda anlamlı oranda düştü. Her üç grupta da sağa lateral fleksiyonda anlamlı düzelme gözlenirken, kombine tedavi grubunda sola lateral fleksiyonda anlamlı düzelme saptanmadı.
Sonuç: Tiyokolşikosid, miyofasiyal ağrı sendromu tedavisinde kullanılabilir ve merhem formu özellikle enjeksiyon uygulanamayan hastalar için iyi bir alternatif oluşturabilir.
Anahtar sözcükler: Lokal enjeksiyon; medikal tedavi; kas gevşetici; miyofasiyal ağrı sendromu; tetik nokta.
1Department of Physical Medicine and Rehabilitation, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey 1İstanbul Üniversitesi İstanbul Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, İstanbul
Submitted - September 1, 2008 (Başvuru tarihi - 1 Eylül 2008) Accepted for publication - November 25, 2008 (Kabul tarihi - 25 Kasım 2008)
Correspondence (İletişim): Ayşegül Ketenci, M.D. İ.Ü. İstanbul Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, 34390 Çapa, İstanbul, Turkey. Tel: +90 - 212 - 414 20 00 / 32712 e-mail (e-posta): DrAysegulKetenci@hotmail.com
Background
Myofascial pain syndrome (MPS) is a disorder char-acterized by hypersensitive sites called trigger points (TPs) at one or more muscles and/or connective tis-sue, leading to pain, muscle spasm, sensitivity, rigor, limitation of movement, weakness, and rarely, auto-nomic dysfunction.[1]
According to the Nuprin report, 53% of the Ameri-can population complains about muscle pain. Among these, 33% and 10% experience pain for more than 11 and 100 days, respectively.[2,3] In one study, out of 172 patients admitted, 54 of them complained about pain and 30% of these were di-agnosed with MPS. The frequency of MPS is 85% in patients admitting to chronic pain centers.[2,4,5] Over 44 million Americans are estimated to have this condition, at a cost of US $47 billion per year.[6] The most common causes of MPS are traumatiza-tion of myofascial structures and acute straining of the muscles. Following acute injuries, painful muscle spasms called TPs can be observed in some individuals.[1]
TPs can be classified as active or latent. An active TP is painful upon palpation and leads to pain, numb-ness, and/or prickling sensation reflecting to the de-fined region, whereas a latent TP can be palpated but is not painful.[2,4]
After injuries, TPs often remain latent within the muscle. When another injury or stress related to the same segment is added to the existing injury, the latent TP exacerbates. Due to these conditions, an unrecognized event may initiate various responses such as very severe pain, long-lasting edema, loss in the range of motion (ROM), and retarded healing. Latent TPs may also be activated by extreme hot or cold or prolonged vibration. Another etiological factor is the micro-traumas caused by daily activities or repetitive motions.[1]
Various theories have been suggested for the patho-genesis of MPS, including ischemic muscle spasm, hyperactivity of muscle fiber, hyperactivity of motor end plate, peripheral sensitization, central sensitiza-tion, and secondary hyperalgesia.[7]
According to the ischemic muscle spasm theory, a
physical trauma such as injury or chronic strain re-sults in continuous release of intracellular calcium and abnormal contraction of the localized part of the muscle. This spasm leads to reflex spasm, pain and damage by the release of serotonin, prosta-glandin, and other inflammatory mediators.[1,4,7-9] Consequently, the resulting inflammation leads to localized fibrosis. The pathological findings of TP biopsies are compatible with this “energy crisis mod-el” and explain the tension in the tensile ligaments in the absence of motor activity.[7] Other reports also support the theories of increased intramuscular mo-tor activity and formation of muscle spasm.
Various treatment methods have been used in MPS. Among these, stretch and spray technique, TP in-jection, dry needling, pharmacological agents, mas-sage, ultrasound, exercise, electrical stimulation, transcutaneous electrical nerve stimulation (TENS), and biofeedback methods have been proven effec-tive.[2,4,8,10]
TP injection is one of the most effective methods in MPS treatment.[2] Several mechanisms have been proposed for the inactivation of TP.[2,4] Nevertheless, the primary objective of the injection treatment is to localize and damage the TP via the needle. The local anesthetic used not only reduces the pain sen-sation during the procedure, but also disturbs the self-stimulating cycle of many TPs.[10]
The medications used for treatment include non-steroidal anti-inflammatory agents, steroids, analge-sics, and antidepressants.[4] The efficacy of myorelax-ants in the treatment of TP pain is controversial. It was suggested that when used at muscle relaxing doses, they could increase the load on the TPs by relaxing the muscles with protective corset function. [4] Botox injection to the TPs, which aims to reduce muscle activity, has become the most studied treat-ment in recent years.[11-14]
Thiocolchicoside (TCC) is a semi-synthetic deriva-tive of colchicoside, a natural glycoside of Superba gloriosa. Its in vitro profile shows affinity for the in-hibitory glycine and GABAA receptors. It has been shown previously that thiocolchicoside induces muscle relaxation without any subjective or objec-tive sedaobjec-tive side effect.[15] In experimental models,
TCC was also found to possess analgesic and anti-inflammatory activities, and in a pharmaco-EEG study, TCC was also shown to be devoid of any sedation.[16] Clinical trials have demonstrated that the therapeutic efficacy of TCC is associated with a good level of safety with sedation rarely reported. [15,17-19]
The objective of this study was to evaluate the ef-ficacy of TCC ointment applied over the TP regions compared to TP injection and to determine whether the efficacy increased when the ointment was ap-plied together with the injection in pain control in patients with acute MPS in the cervical region.
Materials and Methods
Patients who admitted to the outpatient clinic be-tween April 2005 and December 2005 with com-plaints of neck pain, upper back pain, difficulty in sleeping at night, inability to move the neck, and pain during movement during the last one week were included in the study. Patients, 18-50 years old, diagnosed with MPS by the establishment of active TPs in the trapezium and/or interscapular region according to the Simons and Travel criteria, and with 1-8 active TPs, were referred to our clinic. The study was explained to the patients and they were invited to participate. Those that provided written consent for participation were included in the study. Symptoms of significant cervical discopa-thy and osteoarthritis, hemorrhagic diathesis that would impede injection, use of anticoagulants, any known malignancies, use of steroids, immunosup-pressive diseases, drug usage, pregnancy, and any known allergic reactions to thiocolchicoside were the exclusion criteria of the study. The study was ap-proved by the ethical committee of Istanbul Medi-cal Faculty (no: 2005153).
Sixty-five patients were recruited into the study. Pa-tients were randomized into three groups. The first group received TCC ointment onto the TPs twice a day, the second group received 8 mg TCC intramus-cular injection to the TPs once a day (with a black pointed needle), and the third group received both treatments. Evaluation of the patients and applica-tion of the treatments were performed by different physicians. Treatment was applied for 5 consecutive
days and patients were evaluated according to the below-mentioned criteria.
At the beginning of the treatment, patients were evaluated by physical examination, laboratory find-ings, and measurement of the following: severity of pain upon movement and mean pain felt in the last 24 hours using visual analog scale (VAS); cervical ROM using goniometer; and pain severity at TPs using algometer. Algometric and goniometric mea-surements and pain severity assessments with VAS were repeated on the first, third, and fifth days of the treatment. Patient and physician satisfaction was evaluated using the Likert scale at the end of the treatment.
Since performing only manual palpation to measure TP sensitivity was not quite sufficient as an objec-tive criteria for the MPS assessment, the Pressure Threshold Measurement (algometer) device was de-veloped in order to determine the point where the greatest sensitivity and pain were felt both in clinical practice and experimentally. The ratio and sensitiv-ity of the indicator ensure the measurement of both deep and superficial TPs.[1,2,20]
Therefore, VAS assessment of pain severity upon movement and daily mean pain severity was cho-sen as the evaluation criteria.[21] Restriction in ROM and pain upon movement are the most significant complaints of MPS patients. Cervical lateral flex-ions and rotatflex-ions were measured with the goniom-eter. Patients were asked to perform lateral flexions and rotations three times and the mean values of these measurements were evaluated.
Assuming that a difference in the mean decrease in the algometer score upon treatment ranging from 1 to 5 between one group and the other groups would be clinically significant, the study was designed for 60 patients with 20 in each group. Mean drop out ratio was presumed as 10% and thus, 65 patients were recruited into the study.
The results were evaluated using the SPSS 10.0 soft-ware. Spearman correlation, Kruskal-Wallis test, Friedman test, and Intent to Treat (ITT) analysis were used for the evaluation.
ence was also significant at the last evaluation on Day 5 (f: 3.342, p: 0.04). In groups including in-jection treatment, a statistically significant, faster improvement was determined in the pain severity upon movement, compared to the ointment-only group. Pain severity measured with VAS was sig-nificantly improved after the first day in the mono-therapy groups and after the third day in all groups (Table 1, Fig. 1). However, when the evaluation was repeated using the ITT analysis, no significant dif-ferences were observed between the groups in the pain severity upon movement (Day 3 f: 0.403, p: 0.670; Day 5 f: 1.317, p: 0.275). Nevertheless, sig-nificant improvements were observed in all groups after the first evaluation. In addition, although measurements performed with algometer revealed no statistically significant difference between the
Results
In total, 59 patients completed the study. One of the patients receiving TCC ointment did not at-tend the last follow-up; three patients in the oint-ment group plus one patient from each of the other groups were excluded after the first evaluation be-cause they showed complete recovery on their third-day follow-up.
There were no significant differences between the groups at the beginning of the treatment (p>0.05). Although there was no significant difference be-tween the groups in the pressure algometer evalu-ation performed on the third day of treatment, a statistically significant difference was found between the groups in the pain severity upon movement in the last 24 hours (f: 4.196, p: 0.020). This
differ-T v
alues
VAS mean 1- VAS mean 1- VAS mean 1- VAS mov 1- VAS mov 1- VAS mov 1-VAS mean 2 VAS mean 3 VAS mean 4 VAS mov 2 VAS mov 3 VAS mov 4
0.000 1.000 2.000 3.000 4.000 5.000 6.000 7.000 8.000
9.000 Ointment Injection Ointment + Injection
Fig. 1. Improvement in pain evaluation in all three groups.
Table 1. Improvement in pain evaluation in all three groups
Ointment Injection Ointment + Injection
VAS mean 1-VAS mean 2 VAS mean 1-VAS mean 3 VAS mean 1-VAS mean 4 VAS mov 1-VAS mov 2 VAS mov 1-VAS mov 3 VAS mov 1-VAS mov 4 T p T p T p 3.078 0.006 2.017 0.057 1.634 0.117 5.699 0.000 4.776 0.000 3.104 0.005 5.293 0.000 6.858 0.000 5.083 0.000 2.226 0.039 3.520 0.002 3.012 0.007 4.316 0.000 5.698 0.000 5.272 0.000 4.935 0.000 7.910 0.000 6.903 0.000
VAS mov: Pain severity upon movement;
VAS mean: Mean pain severity felt in the last 24 hours; 1. Initial, 2. First day, 3. Third day, 4. Final control.
Discussion
Since patients with MPS are generally young and actively working people, it is very important to rap-idly control the pain in order to reduce the loss to the labor force and prevent the pain from becom-ing chronic. For this purpose, various physical treat-ment methods, stretch techniques, and injections using various medical agents are recommended.[22] For the treatment, various local anesthetic TP injec-tions and dry needling methods had been mostly used until 2000. Some of the studies have also inves-tigated laser therapy, Botox application, and medi-cal treatment methods. Since 2000, Botox applica-tions and various physical therapy applicaapplica-tions have groups, significant improvements were observed in
all three groups at the same level (Table 2, Fig. 2). In the cervical ROM measurements, initial values were close to complete in rotation measurement. Only the changes in lateral flexions were considered in the evaluations. While significant improvement was ob-served in all three groups in right lateral flexion mea-surements, no significant changes were observed in the combined treatment group in left lateral flexion measurements (Tables 3, 4; Fig. 3, 4). Patient and physician satisfaction from the treatment was cor-related particularly with the decrease in mean pain severity. The most commonly observed side effects were nausea and vomiting; however, there were no dropouts or dose adjustment requirements because of the side effects.
Table 2. Mean TP pain thresholds measured with algometer according to groups
Group Control Mean Median SD Minimum Maximum
Initial 3.40 3.00 1.30 1.90 7.60 Ointment Day 1 3.50 3.10 0.90 2.30 5.20 Day 3 3.60 3.20 1.60 1.50 7.80 Day 5 3.70 3.40 1.10 1.80 6.40 Initial 3.60 3.40 0.90 2.30 5.20 Injection Day 1 3.70 3.30 1.70 1.70 7.80 Day 3 4.00 3.50 1.70 1.30 8.50 Day 5 3.70 3.30 1.10 2.50 6.40 Initial 3.60 3.40 1.40 1.70 7.00 Ointment+ Day 1 4.40 4.00 1.70 2.70 9.90 Injection Day 3 4.10 3.70 1.00 2.70 6.20 Day 5 3.90 3.60 1.40 1.70 7.20 Test Control p Initial 0.684 Kruskal- Day 1 0.889
Wallis test Day 3 0.624
Day 5 0.643 Test Group p Ointment <0.001 Friedman Injection 0.001 Ointment+ <0.001 Injection
Fig. 2. Mean TP pain thresholds measured with algometer according to groups.
Ointment + Injection Injection
Ointment
Day 1
Initial Day 3 Day 5
M ean Values 3.00 3.20 3.40 3.60 3.80 4.00 4.20 4.40 4.60
been the most often investigated for treatment pur-poses. The efficacy of local medical treatment was reported in the studies of Dalpiaz. The investigator reported that lidocaine patch was well-tolerated by the patients and was also effective in pain control. [23,24] Since the studies about local medical treatment applications onto the TPs are limited, we decided to conduct this study in order to provide an alternative treatment method for the patients who experienced difficulties with the injections or could not admit for physical therapy.
Another approach for the treatment of MPS is the combination of the treatments. For this purpose,
in-jection and medical treatment or combinations of other treatment methods have been used. Edwards et al. reported that treatment of MPS was more suc-cessful in case of concomitant administration of in-jections in patients performing stretch exercises.[25] Cummings reviewed ‘Needling Therapies in the Management of Myofascial Trigger Point Pain’ in 2001 and stated that “…although the present review does not provide proof of efficacy for any individual technique, it clearly shows that no difference exists between TP injections with different substances, or between dry and wet needling.”[26]
Table 3. Change in right lateral flexion measurements according to groups (all values are in
degrees)
Group Control Mean Median SD Minimum Maximum
Initial 39.20 40 9.6 25 70 Ointment Day 1 41.16 41 8.7 30 70 Day 3 42.68 42 8.7 30 70 Day 5 41.77 45 4.1 35 45 Initial 41.91 45 5.7 20 45 Injection Day 1 43.59 45 5.6 35 64 Day 3 42.90 45 3.9 30 45 Day 5 43.67 45 4.3 30 52 Initial 40.23 42 6.1 20 45 Ointment+ Day 1 41.32 44 5.0 25 45 Injection Day 3 41.36 42 4.5 27 45 Day 5 42.09 45 4.3 30 45 Test Control p Initial 0.051 Kruskal- Day 1 0.147
Wallis test Day 3 0.335
Day 5 0.335 Test Group p Ointment <0.001 Friedman Injection 0.019 Ointment+ 0.009 Injection
Fig. 3. Change in right lateral flexion measurements according to groups (all values are in degrees).
Ointment + Injection Injection
Ointment
Day 1
Initial Day 3 Day 5
M ean Values 38.00 39.00 40.00 41.00 42.00 43.00 44.00
In this study, we aimed to determine whether the ointment form of the muscle relaxant TCC could be an option particularly in patients with injection phobia, contraindications for injections, or with obstacles preventing presentation to the physician for physical therapy or to regular exercise programs. The effects of muscle relaxants have been investigat-ed in previous studies; however, it has been reportinvestigat-ed that the negative impacts of side effects on daily life observed upon oral administration limit their usage. [27] Since TCC has a low degree of sedation side ef-fect as well as a myorelaxant efef-fect in addition to its anti-inflammatory effect, which was shown in
ani-mal studies, we decided to investigate this drug so that patients could benefit from both effects.[28,29] Another route of administration of these drugs is injection. Although studies on the usage of various local anesthetics have been conducted since the be-ginning of the 1980s, the study of Frost in 1986 investigated the use of anti-inflammatory agents in injection form and compared their efficacy with lidocaine. When the investigator assessed the pain severity four hours after the injection, he stated that diclofenac group demonstrated a better improve-ment than the lidocaine group and he related this
Table 4. Change in left lateral flexion measurements according to groups (all values are in
degrees)
Group Control Mean Median SD Minimum Maximum
Initial 40.20 40 8.3 25 62 Ointment Day 1 43.21 43 11.0 30 72 Day 3 44.74 45 10.4 30 74 Day 5 42.55 45 4.1 35 50 Initial 42.22 45 3.9 32 45 Injection Day 1 42.95 45 3.2 35 45 Day 3 43.95 45 2.4 35 46 Day 5 44.38 45 2.3 35 46 Initial 41.50 45 4.9 32 52 Ointment+ Day 1 41.91 45 3.5 35 46 Injection Day 3 41.59 42 3.8 32 45 Day 5 42.18 45 4.1 34 45 Test Control p Initial 0.418 Kruskal- Day 1 0.493
Wallis test Day 3 0.130
Day 5 0.073 Test Group p Ointment 0.001 Friedman Injection <0.001 Ointment+ 0.117 Injection
Fig. 4. Change in left lateral flexion measurements according to groups (all val-ues are in degrees).
Ointment + Injection Injection
Ointment
Day 1
Initial Day 3 Day 5
M ean Values 38.00 39.00 40.00 41.00 42.00 43.00 44.00 45.00 46.00
result to the effect of inflammation in the etiology of MPS.[30] Among the muscle relaxants, Botox is the one used in injection form and also the most extensively studied. Despite the controversial results on its efficacy, in the study of Göbel et al. in 2006, Dysport® application was found to be superior to placebo.[31]
Since the use of two different forms of the same drug was not previously reported in the literature, we also investigated whether the concomitant use of the ointment and injection forms of the same drug would provide more benefit than their single usage. In our study, patients were evaluated three hours af-ter the administration of treatment, which is com-patible with the literature.[23,32] The evaluation of the treatment results revealed that pain severity reduced significantly after the first day in all three groups. However, in the evaluation performed on Day 3, the decrease in the pain severity upon movement in the last 24 hours in the injection group was more than that of the ointment group. The faster reduction of the pain upon movement observed in the injection group was considered to be related to the direct ef-fect of the needle on the TP.[33] However, when the patients who recovered completely and did not at-tend the follow-up on Day 5 were included in the statistical assessment, no significant difference was observed and the same rate of improvement in the patients in the ointment group was determined. This result suggests that the effect of TCC in MPS treatment is independent of the route of administra-tion and that it provides a pain control as fast as that of the local injections.
One of the most important complaints in MPS is difficulty experienced upon movement. Therefore, cervical ROM measurements were also performed for the evaluation of treatment efficacy. Hou and Irnich also used ROM measurement as an evalua-tion criterion in their study and they showed that it increased after the treatment.[34,35] In the cervical ROM measurements in our study, there was sig-nificant improvement in the lateral flexions in all groups, particularly in right lateral flexion. This re-sult is compatible with those of Hou et al.[34] The higher degree of improvement in right lateral flex-ion observed in our study was thought to be relat-ed to the higher incidence of MPS in the left-side
postural muscles of right-handed individuals. It was suggested that right lateral flexion was more sig-nificantly improved after the relief of spasm in the muscles upon treatment.
Patient satisfaction with respect to treatment was mainly determined by the decrease in pain. While 6.5% of the patients evaluated the treatment out-come as perfect, 72.5% evaluated it as good and very good. When patient satisfaction was assessed according to groups, 94.7% of the ointment group, 95.2% of the injection group, and 50% of the com-bined treatment group evaluated the treatment out-comes as good and perfect. The physicians’ satisfac-tion rates were calculated as 94.7%, 95.2%, and 59.1% in the ointment, injection, and combined treatment groups, respectively. Similar results were obtained in the study of Malanga et al., where they administered tizanidine; 89% of the patients and 78% of the investigators evaluated the outcomes as good and very good.[36] It is suggested that these results are associated with the fact that MPS is not considered a serious condition by most physicians, but it is indeed a pathology that worsens the quality of life and has a high chance of cure with appropri-ate treatment.
Side effects were observed in 31% of the patients. The most commonly observed side effect was mild nausea, which was observed mostly in the injection group. Dizziness was reported in only one patient. All side effects were well-tolerated and did not re-quire quitting the treatment. This result is compat-ible with the study of Malanga et al., in which oral tizanidine was administered for the treatment of chronic MPS and no serious side effects upon five-week treatment were reported.[36]
In conclusion, the muscle relaxant TCC can be used in the treatment of MPS and the ointment form may be a good alternative, particularly in patients who cannot receive injections. However, the pa-tients do not prefer the combined usage of ointment and injection forms. More extensive (multi-center, multi-drug) international studies are required on this topic.
References
editor. The management of pain. 2nd ed. Malvern: Lea & Fe-biger; 1990. p. 352-67.
2. Han SC, Harrison P. Myofascial pain syndrome and trigger-point management. Reg Anesth 1997;22:89-101.
3. Taylor H. The Nuprin Report. New York: Lou Harris Associates; 1985.
4. Travell JG, Simons DG. Myofascial pain and dysfunction. The Trigger Point Manual. Baltimore: Williams &Wilkins; 1992. 5. Skootsky SA, Jaeger B, Oye RK. Prevalence of myofascial
pain in general internal medicine practice. West J Med 1989;151:157-60.
6. Magni G. The epidemiology of musculoskeletal pain. In: Voeroy H, Merskey H, editors. Progress in fibromyalgia and myofascial pain. Amsterdam: Elsevier Science; 1993. p. 3-20. 7. Porta M. Treatment of myofascial pain by injection with
boti-linum toxin. Bollington: Adelphi Communications Ltd; 1997. 8. Thompson JM. The diagnosis and treatment of muscle pain
syndromes. In: Braddom RL, editor. Physical medicine and re-habilitation. Philadelphia: Saunders Company; 1996. p. 893-914.
9. Simons DG. Myofascial pain syndromes: where are we? Where are we going? Arch Phys Med Rehabil 1988;69(3 Pt 1):207-12.
10. Simons DG, Travell JG. Myofascial pain syndromes. In: Wall PD, Melzack R, editors. Textbook of Pain. New York: Churchill Livingstone; 1989. p. 368-85.
11. Ojala T, Arokoski JP, Partanen J. The effect of small doses of botulinum toxin a on neck-shoulder myofascial pain syn-drome: a double-blind, randomized, and controlled cross-over trial. Clin J Pain 2006;22:90-6.
12. Qerama E, Fuglsang-Frederiksen A, Kasch H, Bach FW, Jensen TS. A double-blind, controlled study of botulinum toxin A in chronic myofascial pain. Neurology 2006;67:241-5.
13. Kamanli A, Kaya A, Ardicoglu O, Ozgocmen S, Zengin FO, Bayik Y. Comparison of lidocaine injection, botulinum toxin injection, and dry needling to trigger points in myofascial pain syndrome. Rheumatol Int 2005;25:604-11.
14. Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain 2000;85:101-5.
15. Patat A, Klein MJ. Effects of acute and repeated doses of two muscle relaxants chlormezanone and thiocolchicoside, on vigilance and psychomotor performance of healthy volun-teers. Hum Psychopharmacol 1991;6:285-92.
16. Janbroers JM. Review of the toxicology, pharmacodynamics and pharmacokinetics of thiocolchicoside, a GABA-agonist muscle-relaxant with anti-inflammatory and analgesic ac-tions. Acta Ther 1987;13:221-50.
17. Eandi M, Genazzani E, Della Pepa C, Basso G. Ricerca farma-coepidemiologica in fase IV sulla efficacia e tollerabilita’ del prodotto „Muscoril ®. Ort Traum Oggi 1992;12:138-48. 18. Marcel C, Rezvani Y, Revel M. Evaluation of thiocolchicoside
as monotherapy in low back pain. Results of a random-ized study versus placebo. [Article in French] Presse Med 1990;19:1133-6.
19. Ventura R, Leonardi M, Mastropaolo C, Picci M, Vescovini R. Studio clinico controllato sull’uso del thiocolchicoside nella patologia ortopedica. Ortop Traumatol Oggi 1983;3:65-73. 20. Fischer AA. Documentation of myofascial trigger points.
Arch Phys Med Rehabil 1988;69:286-91.
21. Price DD, Bush FM, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain 1994;56:217-26. 22. Baldry P. Management of myofascial trigger point pain.
Acu-punct Med 2002;20:2-10.
23. Dalpiaz AS, Lordon SP, Lipman AG. Topical lidocaine patch therapy for myofascial pain. J Pain Palliat Care Pharmacother 2004;18:15-34.
24. Dalpiaz AS, Dodds TA. Myofascial pain response to topical lidocaine patch therapy: case report. J Pain Palliat Care Phar-macother 2002;16:99-104.
25. Edwards J, Knowles N. Superficial dry needling and active stretching in the treatment of myofascial pain--a randomised controlled trial. Acupunct Med 2003;21:80-6.
26. Cummings TM, White AR. Needling therapies in the manage-ment of myofascial trigger point pain: a systematic review. Arch Phys Med Rehabil 2001;82:986-92.
27. Kvien TK, Viktil K. Pharmacotherapy for regional musculosk-eletal pain. Best Pract Res Clin Rheumatol 2003;17:137-50. 28. Ketenci A, Ozcan E, Karamursel S. Assessment of efficacy and
psychomotor performances of thiocolchicoside and tiza-nidine in patients with acute low back pain. Int J Clin Pract 2005;59:764-70.
29. Trellu M, Filali-Ansary A, Françon D, Adam R, Lluel P, Dubruc C, Thénot JP. New metabolic and pharmacokinetic character-istics of thiocolchicoside and its active metabolite in healthy humans. Fundam Clin Pharmacol 2004;18:493-501.
30. Frost A. Diclofenac versus lidocaine as injection therapy in myofascial pain. Scand J Rheumatol 1986;15:153-6.
31. Göbel H, Heinze A, Reichel G, Hefter H, Benecke R; Dysport myofascial pain study group. Efficacy and safety of a single botulinum type A toxin complex treatment (Dysport) for the relief of upper back myofascial pain syndrome: results from a randomized double-blind placebo-controlled multicentre study. Pain 2006;125:82-8.
32. Turturro MA, Frater CR, D’Amico FJ. Cyclobenzaprine with ibuprofen versus ibuprofen alone in acute myofascial strain: a randomized, double-blind clinical trial. Ann Emerg Med 2003;41:818-26.
33. Raj PP, Paradise LA. Myofascial pain syndrome and its treat-ment in low back pain. Semin Pain Med 2004;2:167-74. 34. Hou CR, Tsai LC, Cheng KF, Chung KC, Hong CZ. Immediate
effects of various physical therapeutic modalities on cervical myofascial pain and trigger-point sensitivity. Arch Phys Med Rehabil 2002;83:1406-14.
35. Irnich D, Behrens N, Molzen H, König A, Gleditsch J, Krauss M, et al. Randomised trial of acupuncture compared with con-ventional massage and “sham” laser acupuncture for treat-ment of chronic neck pain. BMJ 2001;322(7302):1574-8. 36. Malanga GA, Gwynn MW, Smith R, Miller D. Tizanidine is
ef-fective in the treatment of myofascial pain syndrome. Pain Physician 2002;5:422-32.
